The present invention comprises the surprising and unexpected discovery that administration of a cytoprotective prostaglandin to a mammal suffering from or particularly susceptible to certain inflammatory diseases of the large intestine provides a useful method for treatment or prophylaxis of these inflammatory diseases.
Certain pharmacological uses of prostaglandins or prostaglandin analogs in the treatment or prophylaxis of gastrointestinal tract disorders are known in the art. For example, the use of prostaglandin-type compounds effective in reducing gastric secretion and in the cure or prophylaxis of gastric or duodenal ulcers is known. See U.S. Pat. Nos. 3,903,297 and 3,781,429. Further, the concomitant use of prostaglandin-type compounds with a NOSAC (nonsteroidal antiinflammatory compound which is a prostaglandin synthetase inhibitor) is known to be effective to reduce known undesirable gastrointestinal side effects of NOSAC administration. See U.S. Pat. Nos. 3,911,124; 3,917,828; 3,928,588; and 3,927,213.
Finally, the use of PGE.sub.2 to prevent damage to the gastric mucosal barrier in the dog when the gastric mucosal barrier is subjected to attack by aspirin or indomethacin is described in Gastroenterology 68:A-19/876 (April, 1975).
As used herein, the term prostaglandin refers to those cyclopentane-containing carboxylic acids derived from mammalian tissues which are structural derivatives of prostanoic acid: ##STR1## See Bergstrom, et al. Pharmacol. Rev. 20, 1 (1968) and references cited therein. For example, prostaglandin E.sub.2 (PGE.sub.2) exhibits the following structure: ##STR2##
The term prostaglandin analog herein refers to those compounds structurally related to the prostaglandins (in that they exhibit a cyclopentane, or adjacently homologous cycloalkane, ring and a pair of side chains attached to adjacent carbon atoms of the ring) which retain characteristic biological properties of the prostaglandins. See Bergstrom, cited above. Various structural modifications of the prostaglandins are known to produce useful prostaglandin analogs. For example, the replacement of the carboxy with a hydroxymethyl is known, substitution of a methyl, ethyl, or fluoro for a hydrogen at, for example, C-2 or C-16, and replacement of a methylene by an oxa or thia at, for example, C-5 is known. Further, partially deoxygenated prostaglandins are known to be useful prostaglandin analogs. Accordingly, 9-deoxy, 11-deoxy, and 15-deoxy-prostaglandins are known. Finally, there are known prostaglandin analogs wherein the double bonds of, for example, PGF.sub.2.sbsb..alpha. are shifted, e.g., cis-4,5-didehydro-PGF.sub.1.sbsb..alpha., or replaced by triple bonds, e.g., 13,14-didehydro-PGF.sub.2.sbsb..alpha..
As used herein, the term prostaglandin-type compound refers to any prostaglandin or prostaglandin-analog.
The large intestine of all mammalian species is subject to a wide variety of diseases which are characterized by inflammation. For the purposes herein, these inflammatory diseases are characterized by the presence of edema, characteristic inflammatory cells (i.e., leucocytes, histiocytes, and macrophages), and in some cases necrosis and ulceration of the surface epithelium. These inflammatory diseases are readily diagnosed by conventional and readily-ascertainable means to those of ordinary skill in the art. They include, for example, colitis, ulcerative colitis, pseudomembranous colitis, inflammatory bowel disease, tropical and non-tropical sprue and diverticulitis (i.e. inflammation of diverticula).
Those inflammatory diseases are known to be caused by a number of agents which when present in the large intestine, are known to attack its walls, producing the inflammatory disease. These agents include organisms (including viruses and fungi), bacterial toxins, certain pharmaceuticals (e.g., antibiotics and anti-inflammatory steroids), noxious chemicals (e.g., bile salts, and certain household chemicals), certain foodstuffs to which susceptible mammals exhibit an allergic response (e.g., dairy products, wheat gluten, and shellfish), and parasites (e.g., amoeba helminths).
Additional causes of inflammatory diseases include radiation exposure (e.g., x-ray, .gamma.-ray, cosmic radiation, and alpha or beta radiation, particularly when emitted from ingested radioactive materials), neoplastic growth, and invasive traumatic injury to the gut (e.g., from gunshot wounds).
Additionally, inflammatory disease is caused by a wide variety of particulate radiation, e.g., sub-atomic particles (.pi.-mesons) and anti-matter particles (positrons), in addition to the sources described above. Accordingly, an inflammatory disease can result from radiation therapy when, for example, employed in the treatment of cancer.
Finally, the prostaglandin-type compounds are known to be useful pharmacological agents capable of conventional formulations and administration by a wide variety of routes. See U.S. Pat. No. 3,903,297 for a description of typical methods of formulation and administration.